Genetic Modifiers for 22q 11.2 Deletion Syndrome

描述（由申请人提供）：22q11.2缺失综合征（22q11DS，又名velo-cardio-facial syndrome/DiGeorge syndrome）是一种先天性异常疾病，其特征是学习障碍、颅面畸形、免疫缺陷、低钙血症和心流出道缺陷。它发生在1/2- 4000活产婴儿中。大多数受影响的个体都有相同的3mb缺失，这表明缺失间隔内基因的单倍不足是其病因。其中一个最强的候选基因是TBX1，一个包含转录因子的T-box，在胚胎发育期间在咽器中表达。这种疾病是完全渗透性的，但表现性是可变的。该领域最大的挑战之一是确定其各种表达的基础。随机、环境和遗传因素可能改变表型。遗传因素或修饰因子的证据来自动物模型的表型、基因相互作用和Tbx1零突变的遗传背景效应的遗传研究。本研究计划的主要目标是通过在具有典型缺失的人类受试者中进行基因型-表型相关性来鉴定22q11DS的遗传修饰因子。研究一种罕见疾病的部分困难在于获得足够数量的明确的研究对象。我们建议通过创建22q11.2联盟来解决这个问题，从而整合资源。目前已经确定了500个3mb缺失的病例，另外500个3mb缺失的病例将作为该计划的一部分收集。我们将使用Illumina 300,000 HapMap SNP阵列，对300例有明显心脏缺陷和无明显心脏缺陷的患者进行全基因组关联研究。将对700例病例进行生物学复制并进行联合统计分析。我们将根据其他临床畸形对患者进行重新分层。候选基因方法将同时进行，使用Illumina定制的1,536-plex SNP阵列，对1,000名22q11DS中3mb缺失的TBX1遗传通路中的基因进行评估。这是可能的修饰明显畸形的综合征可能赋予易感性偶发性出生缺陷与未知的病因。

DESCRIPTION (provided by applicant): The 22q11.2 deletion syndrome (22q11DS, aka velo-cardio-facial syndrome/DiGeorge syndrome) is a congenital anomaly disorder characterized by learning disabilities, craniofacial malformations, immune deficiencies, hypocalcemia and cardiac outflow tract defects. It occurs in 1/2-4,000 live births. Most affected individuals have the same 3 Mb deletion, suggesting that haploinsufficiency of gene(s) in the deleted interval is responsible for its etiology. One of the strongest candidate genes is TBX1, a T-box containing transcription factor, expressed in the pharyngeal apparatus during embryonic development. The disorder is fully penetrant but the expressivity is variable. One of the greatest challenges in this field is to determine the basis for its varied expressivity. Stochastic, environmental and genetic factors likely modify the phenotype. Evidence for genetic factors or modifiers, derives from genetic studies in animal models in the form of phenocopies, gene interactions and genetic background effects of Tbx1 null mutations. The major goal of this research program is to identify genetic modifiers for 22q11DS by performing genotype-phenotype correlations in human subjects with the typical deletion. Part of the difficulty in studying a rare disorder, is to obtain sufficient numbers of well-defined study subjects. We propose to solve this problem by creating a 22q11.2 consortium, thereby combining resources. Five hundred cases with the 3 Mb deletion have already been ascertained and another set of 500 with the 3 Mb deletion will be collected as part of this program. We will perform a whole genome association study on the DNA from 300 cases divided equally among those with significant heart defects and without, using Illumina 300,000 HapMap SNP arrays. A biological replication on 700 cases and a joint statistical analysis will be performed. We will re-stratify the patient set for other clinical malformations. A candidate gene approach will be undertaken in parallel, to assess genes in the genetic pathway of TBX1 in 1,000, 22q11DS individuals with the 3 Mb deletion, using the Illumina custom 1,536-plex SNP arrays. It is likely that modifiers for the salient malformations in the syndrome may confer susceptibility to sporadic birth defects with unknown etiologies.